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Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy - PubMed

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Review

Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy

Ludovica Morera et al. Clin Epigenetics. 2016.

Abstract

The term epigenetics is defined as heritable changes in gene expression that are not due to alterations of the DNA sequence. In the last years, it has become more and more evident that dysregulated epigenetic regulatory processes have a central role in cancer onset and progression. In contrast to DNA mutations, epigenetic modifications are reversible and, hence, suitable for pharmacological interventions. Reversible histone methylation is an important process within epigenetic regulation, and the investigation of its role in cancer has led to the identification of lysine methyltransferases and demethylases as promising targets for new anticancer drugs. In this review, we describe those enzymes and their inhibitors that have already reached the first stages of clinical trials in cancer therapy, namely the histone methyltransferases DOT1L and EZH2 as well as the demethylase LSD1.

Keywords: Clinical trial; Demethylase inhibitors; Epigenetics; Histone demethylase; Histone methyltransferase; Histone modifications; Lysine methylation; Methylome; Methyltransferase inhibitors.

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Figures

Fig. 1
Fig. 1

Nucleosome structure and principal modification sites on H3, H4, and DNA. The reported writers, erasers, and readers for these modifications are also depicted

Fig. 2
Fig. 2

a Schematic view of DOT1L principal domains. b Structures of the methyl donor SAM, its enzymatic product SAH and of two DOT1L inhibitors. The SAM-like shared moiety is highlighted in bold

Fig. 3
Fig. 3

a Schematic view of EZH2 principal domains. b Structures of EZH2 inhibitors

Fig. 4
Fig. 4

a Schematic view of LSD1 principal domains. b Structures of the unselective LSD1/MAO inhibitor tranylcypromine (TCP), the selective LSD1 inhibitors from Oryzon and GSK and the dual HDAC/LSD1 inhibitor 4SC-202

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